Abstract

Background

Immune checkpoint blockade is developed as standard treatment for non-small cell lung cancer. However immune-related adverse events (irAE) have still unknown complications. Here, we report a patient with lung squamous cell carcinoma who developed neuromyelitis optica spectrum disorder with nivolumab.

Case presentation

A 75-year-old Japanese man with lung squamous cell carcinoma was administered nivolumab as second-line treatment. Two months after treatment with nivolumab, he presented acute paralysis in the bilateral lower limbs, sensory loss. Spinal magnetic resonance imaging showed T2 hyperintense lesions between C5-6 and Th12-L1. He was diagnosed with neuromyelitis optica spectrum disorder (NMOSD) by anti-aquaporin-4 antibody-positive in the serum and other examinations. After treatment, steroid reactivity was poor.

Conclusion

This is the first patient who developed anti-AQP4 antibody-positive NMOSD as a nivolumab-induced irAE. Clinicians should be aware of this kind of potential neurological complication by using immune check point inhibitor and start the treatment of this irAE as soon as possible.

Keywords

Background

Anti-programmed cell death protein 1 (PD-1) antibody nivolumab is now standard treatment as a second-line for non-small cell lung cancer [1, 2]. Although the frequency of adverse events is less than that of conventional chemotherapy, adverse events related to inflammatory response that have not been previously reported may occur. Here, we present a patient with lung squamous cell carcinoma who developed neuromyelitis optica spectrum disorder (NMOSD) with nivolumab.

Case presentation

A 75-year-old Japanese man without any previous neurological illnesses was diagnosed with lung squamous cell carcinoma, stage IIIA, T3N1M0, in the upper right lobe. He underwent two cycles of platinum-based chemotherapy (carboplatin + nab-paclitaxel and carboplatin + docetaxel) as first-line chemotherapy. Thereafter, he was administered nivolumab (3 mg/kg) as second-line treatment. On the day of treatment with nivolumab, he had an infusion reaction as an adverse event. The cancer progressed after one cycle of nivolumab and chest computed tomography (CT) scan showed new lesions in the upper left lobe and an increase in right pleural effusion (Fig. 1) He underwent another round of platinum-based chemotherapy (cisplatin + pemetrexed + bevacizumab) as third-line treatment 3 weeks after the nivolumab treatment. However, he did not complete one cycle of the chemotherapy due to grade 3 constipation according to the Common Terminology Criteria for Adverse Events version 4.1.

Two weeks later, after steroid pulse therapy, spinal MRI showed improvement in the rostral region, but a remnant lesion in the caudal region. Analysis of CSF showed improvement after treatment, but his symptoms of paralysis in the bilateral lower limbs and sensory loss improved only minimally. In this patient, steroid reactivity was poor. Plasmapheresis was performed, but his clinical symptoms did not improve. The patient’s paralysis in the bilateral lower limbs and sensory loss are gradually getting improved after plasmapheresis and continues rehabilitation for six months.

Discussion and conclusions

Adverse events following immune checkpoint blockade are termed immune-related adverse events (irAEs), which are distinct from adverse events caused by conventional chemotherapy. Severe irAEs are rare, and grade 3/4 irAEs are present in less than 3% of patients [3]. Although reports of nervous system disorders such as autoimmune encephalitis and Guillain-Barré syndrome following immune checkpoint inhibitor therapy have been published [4, 5], no reports of nivolumab-induced NMOSD have been described. One report described a case of severe transverse myelitis in a patient with metastatic melanoma who was treated with ipilimumab, another immune checkpoint inhibitor, but anti-AQP4 antibody was not analyzed in this case [6]. A single case of demyelination associated bevacizumab has been reported [7]. However bevacizumab which is anti VEGF (vascular endothelial growth factor)-A agent ameliorates an animal model of multiple sclerosis [8]. Bevacizumab has therefore been proposed as a treatment strategy for NMOSD and Clinical trials of bevacizumab as treatment for NMOSD is still more in progress.

NMOSD is an inflammatory central nervous system syndrome that is associated with serum AQP4 immunoglobulin G antibodies (AQP4-IgG) [9]. CBA and ELISA (100% specific) yielded sensitivities of 68 and 60%, respectively, and sensitivity of 72% when used in combination [10]. In this case, ELISA and CBA for anti-AQP4 antibodies in the serum, which were negative immediately after treatment with nivolumab, became positive 2 months after treatment with nivolumab. This result strongly suggested that NMOSD was secondary to nivolumab. Although NMOSD is often recognized as optic neuritis, this patient only had paralysis in the bilateral lower limbs and sensory loss in the lower body as symptoms of acute myelitis. When early steroid pulse therapy is ineffective, the patient’s condition is often improved by plasmapheresis [11]. Although, spinal MRI and CSF indicated improvement, the patient’s clinical symptoms did not improve.

The precise mechanism causing NMOSD in this case remains unclear, but it is possible that nivolumab would have activated T-cells, especially interleukin-4-secreting Type 2 helper T-cells (Th2) and interleukin-17-secretring T-cells (Th17) leading to B-cell stimulation producing anti-AQP4 antibody and neutrophilic inflammation, based on recent surveys of the disease [12, 13].

To the best of our knowledge, this is the first patient who developed anti-AQP4 antibody-positive NMOSD as a nivolumab-induced irAE. Nivolumab-induced NMOSD may be refractory to treatment. Predicting emergence of NMOSD after nivolumab injection is currently difficult. Therefore, clinicians should be aware of this kind of potential neurological complication by using immune check point inhibitor and start the treatment of this irAE as soon as possible [14].

Funding

The authors received no financial support for the research, authorship and/or publication of this article.

Availability of data and materials

The datasets used and/or the analyzed current case report are available from the corresponding author upon reasonable request.

Authors’ contributions

YN and RY participated in the case collection, drafting, and revising the manuscript. YM, YY and HT performed in the analysis and acquisition of data of the lung cancer. ST, KK, KT, TsS, JS and TK analyzed and interpreted the patient data regarding the NMOSD. TaS and YO participated in drafting and revising all versions of the manuscript. All authors read and approved the final manuscript.

Ethics approval and consent to participate

Reports describing the case of a single patient are exempt from review by the ethics committee of the Asahikawa Medical University. Authors obtained written informed consent and publication consent from the patient.

Consent for publication

Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editor for this journal.

Competing interests

The authors declare that they have no competing interests.

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